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survive a surprise
inspection? An FDA
inspection can be a
nightmare that costs
your company money,
time, and reputation.
Proactive managers
understand the logic
behind FDA regulations
and prepare accordingly.
This three-part survival
guide to inspections
(whether from FDA, a
client, an investor, or a
European agency) will
sharpen your vision
of your companys
regulatory compliance
picture.
20
BioPharm
AUGUST 2002
concerns, problems,
and difficulties are
those that FDA
inspectors look out
for. Then we make
sure you know how
to address those
issues properly (see
the Prepare for an
FDA Inspection
sidebar).
Much of an
inspection focuses
on a companys
quality systems. By
definition, a quality
system is a program
that addresses the
needs and elements
of a specific part of a
manufacturing operation. A training
program, for example, is a quality
system a quality
system that defines
in detail how the
Massoud Lavian and Paul W. Allen
company will ensure
or many companies, coping with an
that its employees have the proper knowledge to
FDA inspection can be a nightmare.
carry out their responsibilities.
Workloads increase significantly before,
Pharmaceutical and biotechnology companies
during, and after an inspection, and
typically determine how they are going to
there is always the potential that a major
classify their quality systems. Quality systems
regulatory economic downfall could be
typically include standard operating procedures
part of a companys future if the inspec(SOPs), monitoring programs, change control
tion yields negative or mixed results.
policies, validation programs, training, deviation
This three-part series addresses common
and investigation programs, and consistent docuissues that arise during an FDA inspection and
mentation practices.
provides advice on how to prevent those difficulOur survival guide, therefore, also begins by
ties. Part 1 describes those actions and programs
focusing on quality systems: on determining
that must be part of routine operations, whether
those quality systems needed and in place, on
an inspection is imminent or not. Part 2 focuses
ascertaining how practical particular quality
on inspection day and what to do during that
systems are, and on checking how well those
examination. Part 3 follows the aftermath
quality systems have been implemented and
responding to inspection results, implementing
followed. It is the responsibility of a companys
corrective actions, and learning from the entire
management to ensure that quality systems are in
inspection process.
place, reviewed periodically, upgraded, impleWe dont try to predict all the possible
mented, and followed.
questions and concerns that can come up during
STANDARD OPERATING PROCEDURES
an inspection. Even an FDA inspector couldnt
SOPs are a critical quality system feature, and
do that. Instead, we discuss common deficiencies.
they frequently get inspected their contents,
This survival guide ensures that you know what
the quality of their preparation, and how well
an inspection is, what aspects of company operathey are followed. SOPs are detailed documents
tions (equipment, documents, tests) are likely to
that
specify operating guidelines and instructions
be inspected, and what the most common
for every procedure within the company.
Design
Development
Testing
Installation
Maintenance
Vendor audit
Source code
Configuration
Performance
qualification
Routine audits
Functional
requirements
Unit test
enhancements
Stress test
Vendor RFP
Vendor
documentation
Change control
Traceability matrix
SOP development
Configuration design
SOP validation
Validation summary
report
Program design
specifications
21 CFR Part 11
assessment
Security plan
Data migration plan
Tool description
Change control
process
Audit trail
specifications
Problem report
resolution
Training
Operational
qualification
Hardware description
Installation
qualification
Acceptance criteria
BioPharm
AUGUST 2002
21
VALIDATION PROGRAMS
At your next staff meeting, ask your coworkers,
Does our company have a comprehensive
validation program in place? Be prepared for
several interesting responses.
Validation programs are arguably what inspectors are most interested in when they visit your
company. During validation, critical parameters
and acceptable ranges are established for
processes and equipment. The quality of the validation program indicates how tests are performed
and documented, how deviations are handled, and
how conclusions are reached. How a validation
To Prepare for an FDA Inspection
This list of five To Do or Not to Do items will help you prepare for an
FDA inspection.
Dont procrastinate. Never wait until the last minute to prepare for a scheduled
it either does not exist or never took place. Follow good documentation
procedures (GDP). Technology makes it easy to follow established formats and
requirements.
Work with QA, not against it. The QA department is responsible for overseeing
Before an Inspection
A proactive manager asks questions
about the companys validation
protocols well before an inspection is
anticipated. Questions such as the
following will shine a light on any fog in
your companys regulatory compliance
picture.
Is our validation approach sound? That
is, are we testing what we should be
testing? Is our validation approach in line
with current industry practices and with
the latest guidelines?
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AUGUST 2002
BATCH RECORDS
Inspecting Deviations
Following are typical
questions that an
experienced inspector has
in mind when inspecting a
companys deviation
management and
corrective action plans.
Is a formal investigation
program in place to address
deviations?
Are deviations noticed by
chance, or are they detected
in a timely manner during
systematic evaluation?
How was the effect of the
deviation determined? Who
approved that determination?
Was trend analysis
conducted under a formal
program or SOP? Was there
a global approach to
determining whether a
deviation was an isolated
incident? Was a trend
detected?
Was the root cause of a
deviation found and
corrected?
Who was involved in
determining corrective
action? How was the
corrective action decision
reached?
Was the investigation of the
deviation performed and
concluded in a timely
manner?
Was corrective action
universal? Was it effective?
What was done to prevent
the deviation from happening
again?
What measures were taken
to assess the corrective
action to ensure that it would
not be the source of future
deviations?
Were all of the above actions
properly documented?
TRAINING
A review of the most recent citations issued to
companies by FDA shows that many of the issues
they cite relate to human error (4). The key to
overcoming human error problems is proper and
frequent training.
Inspectors examine training records when they
reach the conclusion that improper use of the
machinery or human errors are the cause of a
cited issue. The inspector in these cases will naturally ask if proper training was conducted. Therefore, you need to ask the questions first.
When evaluating your companys training
program, be sure to document your responses to
training questions. Does a formal program
mandate training? Does the training program
specify who needs to be trained and on what
equipment or processes? Are training materials
presented properly by a qualified trainer? Do the
training records indicate who was trained and on
BioPharm AUGUST 2002
23
SOP Failures
Reviewing FDA warning letters (4) to other companies can help ensure
that your company isnt making the same mistakes. The most frequently
cited SOP failures include:
Lack of global or corporate policies (at upper management level) for all major
elements of the companys operation: validation, change control, batch release,
and other functions
Lack of local (departmental or functional) level procedures for every job and
task in all company operations
Lack of clarity or specificity in SOPs, which must not require or allow individual
interpretations
Lack of proper training (when employees covered by an SOP are not trained on
the contents of that document)
Lack of assigned responsible functions for each specific task (SOPs must
assign specific responsibilities, defining who is responsible for carrying out each
particular task)
Lack of or incomplete document history file (each SOP must have a history file
that includes the entire history of that document, the reasons for any changes,
and approval documentation)
Use of outdated SOPs (an SOP system must be properly set up to archive and
remove outdated SOPs from circulation; audit trails now allow this to happen
automatically, if the information technology (IT) team sets them up properly); a
mechanism must be in place to ensure that the latest version of each SOP is
available and in use at all times
Failure to follow SOPs (all SOP instructions must be followed word for word
without exception); in extreme cases of deviation, documentation on what
happened, why it happened, what the effect was, how it was corrected, and who
approved the corrective action must be provided; SOPs should describe how to
handle deviations, actions that must be taken, and necessary approval levels
A majority of inspection observations relate to SOPs that were not followed and
the lack of appropriate instructions when a deviation occurred.
Corresponding author
Massoud Lavian is assistant director
of compliance and Paul W. Allen is
the managing partner responsible for
life sciences at Clarkston Consulting
(a management and IT consulting firm
specializing in FDA and validation
issues), 595 Market Street, Suite 1450,
San Francisco, CA 94105,
310.869.4060 or 888.486.1141,
ext. 4931, fax 415.354.8743,
mlavian@clarkstonconsulting.com,
www.clarkstonconsulting.com.
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AUGUST 2002
CHANGE CONTROL
Throughout the manufacturing operation and
within all production processes, change is
inevitable. New process steps, changes in equipment, and improvements or corrected inadequacies
all cause change within a companys operations.
A formal program must be in place to handle
changes. Inspectors often focus on this facet of
production during an inspection. Inspectors
reviewing a companys change control programs
will ask if a formal change control program is in
place, who administers the program,
and
which
department has ultimate authority over
change control.
They will ask how
the effects of a
change are assessed, what steps
are taken to minimize or prevent additional impacts,
how decisions are
made, the thought
processes behind
change, and who approves them. And, as in all
other production processes reviewed, an inspector
will want to know how the entire change event, the
actions taken in response to the change, and the decisions made regarding the change have been
documented.
Continued on page 49
DOCUMENTATION PRACTICES
People in the biopharmaceutical industry often
joke that, In God we trust, everything else must
be documented. That phrase speaks for itself
and for the mountains of documents that regulatory compliance requires.
FDA inspectors insist on reviewing documentation processes. Documents are the only proof
that companies have with which to defend their
practices and operating procedures. Therefore no
amount of effort put into preparing proper documents is in vain. Long before an inspection,
review your companys documents . . . and then
review them again. Find and fill document gaps,
obtain approval signatures, be clear and, most
of all, be factual in your documentation. Always
remember, If you dont have the proper documentation for an action or item, you dont have
that item, or no action was taken.
REFERENCES
(1) Current Good Manufacturing Practice in
Manufacturing, Processing, Packing, or Holding of
Drugs, Code of Federal Regulations, Food and
Drugs, Title 21, Part 210 (U.S. Government Printing
Office, Washington DC), revised 1 April 2001.
(2) Current Good Manufacturing Practice for Finished
Pharmaceuticals, Code of Federal Regulations,
Food and Drugs, Title 21, Part 211 (U.S.
Government Printing Office, Washington DC),
revised 1 April 2001.
(3) Biological Products, Code of Federal Regulations,
Food and Drugs, Title 21, Part 600 (U.S.
Government Printing Office, Washington DC),
revised 1 April 2001.
(4) FDA Warning Letters. Available at www.fda.gov/
foi/warning.htm (accessed May 2002). BP
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